The cancer associate stroma has come to light as a dynamic partner in the evolution of malignancy. Gene expression data have elucidated functional signatures that are associated with specific biology, including that associated with stroma and have recently been found to have prognostic significance. We have developed the technical tools to quantify percent enhancement values in normal appearing stroma from CE-breast MRIs. In our previously published work, we showed that mean global enhancement values of the breast stroma were associated with disease-free survival in patients with breast cancer receiving neoadjuvant chemotherapy. This study revealed that host breast tissue had properties measurable by MRI that were prognostic. We extended these investigations further to evaluate the stroma in relationship to tumor proximity. In our current preliminary data, we found that in all patients, percent enhancement decreased from the periphery of the tumor with increasing distance, and that this region was histologically associated with significantly increased angiogenesis. We hypothesize that both global host tissue properties, and cancer- associated stroma, adjacent to the tumor, are critical to tumor biology and will be prognostic for outcomes in patients with locally advanced breast cancer. In this proposal, our primary endpoints will be to address whether MRI-characterized stroma and gene expression array signatures are associated with relapse free survival in patients with invasive breast cancer enrolled in the CALGB 15007/ ACRIN 6657 Contrast-Enhanced Breast MRI and Correlative Science Studies to Characterize Tumor Response in Patients Undergoing Neoadjuvant Treatment for Locally Advanced Breast Cancer ("ISPY" trial). PUBLIC HEALTH RELEVANCE: This project addresses the hypothesis that the host tissue and cancer-associated stroma have biologic properties that are prognostic and predictive of outcomes in breast cancer patients. Our strategy will be to apply the novel tools we have developed using MRI to a completed clinical trial that enrolled invasive breast cancer patients to receive neoadjuvant chemotherapy and undergo serial tumor biopsy and breast MRI, the CALGB 15007/ ACRIN 6657 Contrast-Enhanced Breast MRI and Correlative Science Studies to Characterize Tumor Response in Patients Undergoing Neoadjuvant Treatment for Locally Advanced Breast Cancer ("ISPY" trial). We will use pre-treatment MRIs to measure enhancement values globally and topographically for each patient. Quantitative measures will be associated recurrence free survival, and a multivariable regression model that accounts for other prognostic factors will be determined. Then, gene expression array data from the pre-treatment tumor biopsy will be analyzed for expression array signatures and their association with outcomes. Gene expression signatures with biologic function will also be investigated, and all signatures will be correlated with MRI phenotypes and outcome. These studies will allow us to validate whether stromal MRI measurements are prognostic, and to determine whether cancer- associated stromal gene expression signatures improve prediction of outcomes.